The Peter Attia Drive - #180 - AMA #28: All things testosterone and testosterone replacement therapy

Episode Date: October 18, 2021

In this “Ask Me Anything” (AMA) episode, Peter and Bob discuss all things related to testosterone: what happens when testosterone levels are low, and the potential benefits and risks of testosterone replacement therapy (TRT). They explain the physiology of testosterone, how it works, and how its level changes over the course of a person's life. They have a detailed discussion about existing literature, which reveals vast potential structural, functional, and metabolic benefits of testosterone replacement therapy. They also take a very close look at potential risks of this therapy, with a focus on the controversial effects on cardiovascular disease and prostate cancer. If you’re not a subscriber and listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or on our website at the AMA #28 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: A primer on the hormone testosterone and how it influences gene expression [3:30]; How the body naturally regulates testosterone levels [11:30]; The defining threshold for "low testosterone," how low T impacts men, and why free testosterone is the most important metric [16:15]; When it makes sense to treat low testosterone [26:00]; The structural and metabolic benefits of testosterone replacement therapy [29:15]; Body composition changes with TRT [45:30]; Changes in bone mineral density with TRT [48:15]; The metabolic impact of TRT: glucose, insulin, triglycerides, and more [52:30]; A study investigating testosterone replacement therapy for prevention or reversal of type 2 diabetes [59:30]; The impact of TRT on metabolic parameters and body composition—A study comparing results from continuous vs. interrupted treatment [1:07:15] The controversy over TRT and cardiovascular disease [1:21:45]; Two flawed studies that shaped perceptions of risks associated with TRT [1:44:15]; The controversy over TRT and prostate cancer [1:56:45]; Other potential risks with testosterone replacement therapy [2:02:15]; and More Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/ama28/  Subscribe to receive exclusive subscriber-only content:  https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to a sneak peek, ask me anything, or AMA episode of the Drive Podcast. I'm your host, Peter Atia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to peteratia-md.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode. Welcome to Ask Me Anything episode number 28. I'm joined once again by Bob Kaplan. In this episode, we talk about all things related to testosterone and its replacement. So we talk about the physiology of testosterone, how it works. We talk about the epidemiology of testosterone, how it changes in level over the

course of a person's life. We talk about what happens when testosterone levels are low and what happens when it is replaced. So we talk about the benefits of testosterone. We also talk about the risks of testosterone, mainly focusing on two risks, cardiovascular and prostate cancer. Now, a couple things to mention before we jump into this one, this is a pretty important episode, whether or not you have low testosterone or not not because almost everyone at some point in the course of their life will get to a point where their levels get to a level that is defined as low and we'll talk about what those cutoffs are. Therefore I think that whether it's something that pertains to you or something that pertains

to someone that you care about, whether it's a spouse or a family member or relative or friend, I think it's worth getting smart on this because there is a lot of misinformation out there on this topic just as there is a lot of misinformation out there on the topic of hormone replacement therapy for women. So yes, this is a pretty male-centric discussion because we focus on testosterone replacement therapy and well testosterone does play a very important role

in women. For this episode, we are focusing almost exclusively on the role of testosterone in men. Now, this is not an episode where we get into case studies. I'm not going to be going over clinical studies, though I do pepper in a lot of clinical vignette, so to speak all the way through it. So I talk a lot about the different ways in which testosterone was replaced, the pros and cons of different ways it's replaced, injections versus patches versus gels versus oral and different manners in which it's dozed. So the frequency would be to dose it and all of these things.

Again, this podcast is probably much more geared towards males and we're of course aware that our audience is only half male. So that said, just as I suggested to males when we did the HRT discussion, it's something that you ought to be aware of because you undoubtedly know a female who is going to go through menopause. And similarly, if you're a female,

you undoubtedly know a male who is going to experience their own version of menopause, which is to say their testosterone levels are going to go down. version of menopause, which is to say their testosterone levels are going to go down and the question will be, should anything be done about it. So if you're a subscriber and you wanna watch the full video, this podcast, you can find it on the show notes page.

I highly recommend that like many of the recent AMAs, this one will be better served by watching it on video because there's just so much data that Bob and I present and we do it in the form of graphs and figures. If you're not a subscriber you can still watch a sneak peek of this on our YouTube page but again you'll get more out of this by watching it on video than listening it if you are a subscriber. So without further delay, I hope you enjoy AMA number 28. Hey Peter. Hey Bob. Are you ready for another AMA? Sure am, man. Okay, I think we're going to get to maybe one big topic here. We've got a bunch of questions around one topic, but I think we can distill it down into, can you

do a deep dive on testosterone or testosterone replacement therapy? And can you do it under six hours? I think it'll be tight, but I think we can do it. Yeah, super interesting topic. And one that probably just generates almost as much confusion as the hormone replacement therapy question does on the female side. So we've already had a great podcast that debunks a lot of the myths around hormone placement therapy for paramanoposal and postmenoposal women. And I think in some ways this will be the equivalent podcast for testosterone replacement therapy in men. So with that said, what this will not be is kind of a review of, you know, nonstop case studies of how it's done in the real world.

I think we'll reserve that for a subsequent podcast probably in the form of an AMA, but remains to be seen because I think sometimes there are multiple ways to go about doing this, but I think for the purpose of trying to get through an enormous body of literature, I think we'll reserve this to what testosterone is, how it works, what's the kind of epidemiology of testosterone deficiency, i.e. what does it look like by decade? What are the implications of that? What are the benefits of replacement and one of the risks

of replacement? If we can get through that today, I will be delighted, but we'll see. I know it's ambitious. Me too. Yeah, and I think that hormone replacement therapy is a good example here, where I think with HRT, a lot of women worry about, I think it was breast cancer risk and we've talked a lot about that. And here with TRT, a lot of the questions were, is TRT right for me if I'm worried about cardiovascular disease or prostate cancer? And there's a lot of controversy about that stuff. So be good to dig into it. And I know that for this one, you sent me over some slides the other day that was helpful and I think it will be helpful for the people hopefully watching this.

I think this is definitely another one of those things where it's fine to listen, but I think the level of detail will lend itself to being able to actually see what's going on both in figures and tables as we sort of draw things out of the literature. So take it away, Bob. Okay, so the first question is pretty basic. What is testosterone? So testosterone is a hormone and it's a steroid hormone. So it's derived from the cholesterol family as many hormones are. And it's synthesized in a number of steps. I'll be honest with you, I don't actually remember anymore how many steps it takes to create testosterone

out of cholesterol. But what's really important is that it exerts its effect through binding to an androgen receptor. So because it is a hydrophobic molecule, it basically makes its way into the cell easily. It diffuses into the cell quite simply, meaning it doesn't require a channel or a receptor on the cell membrane to make its way inside. So, as we've talked about a lot with respect to lipids and lipoproteins, cholesterol can't make its way through the bloodstream, the way glucose can or the way

electrolytes can, you know, for example sodium, potassium, and those things, because they're soluble in water, they're therefore soluble in the bloodstream, in plasma, and they don't need chaperone or carrier proteins. But cholesterol does, and that's of course why it travels in things called LIPA proteins. And similarly testosterone needs to be bound primarily to carrier proteins. And there are really two dominant carrier proteins that bind testosterone and carry it around. One is called sex hormone binding globular, or SHBG for short. And the other is albumin. And directionally speaking, SHBG is responsible for about two-thirds

of the carrying capacity, whereas albumin is about one-third. But what's important is knowing that it's only the unbound portion of testosterone that is able to actually exert the biological influence. So we pay very special attention to how much testosterone is quote unquote free. And free is defined as the testosterone that is neither bound to SHBG or Albumin, whereas there's another term that many people who have had a blood test may notice something called bioavailable testosterone. And that's the portion that is unbound to SHBG, but remains bound to albumin or is free. In other words, free testosterone, which is a tiny amount, it's

typically one to two, maybe three percent of total testosterone, is that which is completely unbound. Whereas bioavailable includes that tiny fraction plus the much larger fraction that is bound to Albumin. I would say from a clinical standpoint, I find that symptoms track more with free testosterone than bioavailable, but honestly, they're close enough in terms of their prediction of what's going on that if you're using a lab that relies on one versus the other, it's probably okay. The lab that we use uses total testosterone, of course, but free testosterone. And it's really the free number that we're paying most attention to.

So let's go back to how testosterone works. So it makes its way into the cell. And then it binds to an Androgen receptor. And this receptor is outside of the nucleus. It undergoes this conformational change and it causes things called heat shock proteins to be dislocated. They get transported into the cell and then something called the dimerization takes place.

And that's just a fancy way of saying, a new molecule is created by the fusion, and it doesn't have to be covalent, it can be non-covalent, but the fusion of two molecules that look very much alike. So this Androgen receptor dimer now makes its way into the nucleus and binds with something called a hormone response element. And that's what actually

turns on and off gene transcription. And that's effectively what testosterone is doing. It is up or down regulating genes that are responsible for a number of things, but the most obvious of these are kind of the anabolic or growth characteristics. Now, there's something else I think we're mentioning here, Bob, which is the presence of another hormone here called dihydro testosterone or DHT. Now, DHT is anywhere from, oh, I don't know, I think it's about three to six times more powerful than testosterone. And by powerful, I just mean has a greater binding

affinity for the end region receptor. And so, DHT is something that is converted from testosterone using an enzyme called 5 alpha reductase, which I think we're going to get to that later, Bob. So probably not going to go into much detail on that now. But I think that that that's probably as much as I want to say on this topic only because we could go a lot deeper into it, but I'm not sure it really adds much value to the clinical questions that we're going to want to get to unless there's anything else that you have seen with respect to questions that people have about this. Not a lot of questions about that more around the practical stuff. Like, what is low T and, you know, what happens if you replace it? Okay. It's probably worth also saying just something about

how the body regulates this at a macro level. And I think you have a slide on that. Do you mind pulling that up? Yes. So in this schematic, you can see basically the feedback loop that exists. schematic, you can see basically the feedback loop that exists. So obviously you have the central nervous system, but specifically the hypothalamus. And the hypothalamus in response to low testosterone will secrete gonadotropin releasing hormone. It secreets that to another part of the endocrine system called the pituitary gland, which is divided into two pieces, an anterior and a posterior. So in the anterior pituitary gland, in response to gonadotropin releasing hormone, two other hormones are released. And these are hormones that most people might even be familiar with because you'll see them on the blood test. One is called LH, or luteinizing hormone. The other is called FSH, or follicle stimulating hormone.

So LH and FSH are released from the anterior pituitary gland into the bloodstream, and their targets are two specific types of cells in the testes. One of them is called the Certule cell, and one of them is called the Certule cell and one of them is called the latex cell. Now the Certule cell is responsible for secreting growth factors that further stimulate the latex cell. And LH directly acts on the latex cell. And the net result of this is the production of testosterone. And as you can see in this figure, it's actually a little more sophisticated, right? There's more going on here.

So the and regions that are produced by the latex cell testosterone can undergo what's called aromatization, which is the process by which they are turned into estrogens using specific enzymes that will sort of not get into at the moment. But an obvious byproduct of testosterone creation is the co-creation of estradiol. I guess the most important thing I want to say on this figure is that when testosterone is low, the feedback cycle to the brain ultimately is to ramp up the secretion of LH and FSH. secretion of LH and FSH. Conversely, when testosterone is high, the signal that sent back is to inhibit the production of these things. So, this is a very important point to understand clinically. If a person is supplementing with testosterone, it is usually very obvious to tell this from their blood work because they have

unmeasurable levels of LH and FSH and usually high levels of testosterone. Now, at some point, this becomes a permanent issue. In other words, at some point, if a person is taking exogenous testosterone for long enough, their body will lose the ability to make its own. Now, I think we'll come back to that a little bit later, but I just want to point out that this is a regulated process through a feedback loop. Another way to look at this sort of clinically is when you see patients who have relatively high LH and high FSH, but low testosterone. So in that situation, high LH, high FSH, low testosterone,

the problem is usually in the testes. Conversely, when you see low testosterone, but low LH and low FSH, the problem is usually central, meaning there's something in the brain that isn't working, and of course, I'm being a little tongue-in-cheek when I say that because it's not really the brain that's not working. But there's something in that pathway either at the GNRH level or at the pituitary level. And I will say that the most common thing that we see clinically that results in that picture, i.e. low testosterone, but with an inappropriately low LH and FSH,

is sleep deprivation and hypercortisolemia, i.e. lots of stress. So those are unfortunately, kind of ubiquitous clinical situations. We see a lot of people that have insufficient sleep or insufficient quality of sleep, and or high levels of cortisol and stress, which by the way are difficult to disentangle sometimes from poor sleep, and that can result in the

brain not sending the right signal to the testes. But that's important from a clinical perspective because how we treat low testosterone when we do make the decision to treat it is highly dependent on being able to differentiate between those two paths. Any other questions that have come up on that particular topic, Bob? No, I think that's it. Okay. So where to next? So next we have the questions of, okay, so what constitutes low test Osterone? And I think you just made a distinction there, but maybe just from a clinical level, if we're looking at numbers wise, if somebody's looking at a panel, what is low test Ostrone? Well, so this is interesting. I will say that most of the literature focuses on low total test Ostrone. And I think that's probably because it's more

commonly measured, it's easier to measure. And it's basically the one thing that's always going to be measured. Whereas I think not all the time or physicians also measuring free testosterone or bioavailable testosterone. Again, my bias is to measure free testosterone because that's actually the testosterone that makes its way into the cell. But if you pull up the table that looks at total testosterone levels, we'll get a sense at how wide the range is across all age groups. Thank you for listening to today's Sneak Peak AMA episode of the Drive.

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